NorUDCA promotes degradation of α1-antitrypsin mutant Z protein by inducing autophagy through AMPK/ULK1 pathway

Alpha-1 Antitrypsin (alpha 1 AT) Deficiency is a genetic disease in which accumulation of alpha 1 AT mutant Z (alpha 1 ATZ) protein in the ER of hepatocytes causes chronic liver injury, liver fibrosis, and hepatocellular carcinoma. No effective medical therapy is currently available for the disease. We previously found that norUDCA improves the alpha 1 AT deficiency associated liver disease by promoting autophagic degradation of alpha 1 ATZ protein in liver in a mouse model of the disease. The current study unravels the novel underlying cellular mechanism by which norUDCA modulates autophagy. HTOZ cells, modified from HeLa Tet-Off cells by transfection with the resulting pTRE1-ATZ plasmid and expressing mutant Z proteins, were studied in these experiments. The role of norUDCA in inducing autophagy, autophagy-mediated degradation of alpha 1 ATZ and the role of AMPK in norUDCA-induced autophagy were examined in the current report. NorUDCA promoted disposal of alpha 1 ATZ via autophagy-mediated degradation of alpha 1 ATZ in HTOZ cells. Activation of AMPK was required for norUDCA-induced autophagy and alpha 1 ATZ degradation. Moreover, mTOR/ULK1 was involved in norUDCA-induced AMPK activation and autophagy in HTOZ cells. Our results provide novel mechanistic insights into the therapeutic action of norUDCA in promoting the clearance of alpha 1 ATZ in vitro and suggest a novel therapeutic approach for the treatment of alpha 1 ATZ deficiency disease and its associated liver diseases.